The role of microglial- and neuron-specific MyD88 signaling in tauopathies

小胶质细胞和神经元特异性 MyD88 信号传导在 tau蛋白病中的作用

• 批准号: 8382973
• 负责人: Kiran Bhaskar
• 金额: $ 4.28万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-05-01 至 2012-09-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8382973
• 关键词: Ablation; Age; Alzheimer' s Disease; Applications Grants; Attenuated; Back; Behavioral; Brain; Brain Injuries; CX3CL1 gene; Cell Death; Cells; Cognitive; Communication; Drug Delivery Systems; Encephalitis; Etiology; FK506; Feeds; Functional disorder; Future; Genes; Genetic; Goals; Human; Hypoxia; IRAK1 gene; Immunosuppressive Agents; Impaired cognition; Impairment; Inflammation; Inflammatory; Interleukin-1; Interleukin-1 Receptors; Link; Lipopolysaccharides; MAP Kinase Gene; MAPK14 gene; Mediating; Microglia; Molecular; Molecular Conformation; Mus; MyD88 protein; Myelogenous; Nerve Degeneration; Neurodegenerative Disorders; Neurofibrillary Tangles; Neurons; Nuclear; Outcome Study; Pathology; Pathway interactions; Pharmaceutical Preparations; Play; Process; Production; Progressive Supranuclear Palsy; Prosencephalon; Protein Kinase Interaction; Receptor Signaling; Role; Signal Pathway; Signal Transduction; Tauopathies; Testing; Transgenic Mice; adapter protein; age related; base; behavioral impairment; cognitive function; corticobasal degeneration; cytokine; feeding; hTau Mice; human CX3CR1 protein; human MAPK14 protein; inhibitor/antagonist; insight; mouse model; neurofibrillary tangle formation; neuroinflammation; response; tau Proteins; tau phosphorylation; therapeutic target; toll-like receptor 4

DESCRIPTION (provided by applicant): Prominent filamentous inclusions of microtubule-associated protein tau (MAPT) and neurodegeneration are hallmarks of many neurodegenerative tauopathies. Although the exact etiology of many of these tauopathies remains elusive, neuropathologically they are characterized by intracellular aggregates of hyperphosphorylated MAPT, neuroinflammation and cell death. Increasing evidence suggests that neuroinflammation may directly contribute to the pathophysiology of neurodegenerative tauopathies. However, these studies are largely correlative, and do not provide direct evidence of the role of neuroinflammation in the neurodegenerative disease process. We have recently provided compelling evidence that neuroinflammation, cell-autonomous to microglia, accelerates MAPT phosphorylation, aggregation and behavioral impairment in a mouse model of tauopathy (hTau). Notably, the effects of microglial activation on MAPT pathology were enhanced when mice were deficient for the microglial-specific fractalkine receptor, CX3CR1. We also demonstrated that interleukin-1 (IL1) released by reactive microglia induces MAPT phosphorylation in primary neurons via activating neuronal IL1 receptor (IL1R) and p38 mitogen activated protein kinase (p38 MAPK) pathway. Taken together, these results suggest that inhibition of neuronal IL1R/p38 MAPK may represent a unique potential drug target for human tauopathies. Numerous studies have established that Myeloid Differentiation primary response gene 88 (MyD88) is a key downstream adapter protein for IL1Rs as well as upstream for p38 MAPK activation. Recent studies have suggested that genetic deficiency of MyD88 is protective against hypoxia induced brain injury and mouse model of systemic inflammation. However, the role of MyD88 in mediating IL1 induced MAPT pathology is unclear. Also not clear is whether or not microglial-derived IL1 feeds-back to microglia themselves to induce self-propagating IL1 signaling that contributes to neuronal MAPT pathology and neurodegeneration. Based on our recent study that microglia-specific neuroinflammation is sufficient to induce neuronal MAPT pathology and cognitive impairment via IL1-p38MAPK pathway, the goal of the current proposal is to specifically target microglia-specific and neuronal-specific IL1R signaling via targeted, cel-specific deletion of MyD88 and study its effect on p38 MAPK activation, MAPT pathology, neuroinflammation, neurodegeneration and cognitive function in a mouse model of tauopathy (hTau) under two specific aims. 1) Study the effect of forebrain neuron- restricted deletion of MyD88 in hTau mice on MAPT pathology, neuroinflammation, neurodegeneration and behavioral function at different ages. 2) Study the effect of microglia-restricted deletion of MyD88 in hTau mice on MAPT pathology, neuroinflammation, neurodegeneration and behavioral function at different ages. These studies will provide greater understanding of cell autonomous contribution of IL1R/MyD88 signaling in tauopathies and determine whether MyD88 can serve as a potential therapeutic target against inflammation- mediated MAPT pathology in human tauopathies. PUBLIC HEALTH RELEVANCE: Accumulating evidence suggests that the age-related brain inflammation may play an important role in tau-mediated neurodegeneration in numerous human tauopathies. A recent study from our group has provided compelling evidence that microglia-specific neuroinflammation accelerates tau pathology and cognitive impairment in humanized mouse model of tauopathy (hTau). Notably, interneukin-1 (IL1) released from activated microglia is responsible for upregulating neuronal p38 mitogen activated protein kinase (p38 MAPK) and tau hyperphosphorylation via IL1 receptor (IL1R) signaling pathway. In the current study, the effect of forebrain neuron- and microglia-specific ablation of IL1R signaling via deletion of an IL1R adopter protein, MyD88, on tau pathology, neurodegeneration and behavioral function will be studied in the hTau mouse model of human tauopathy. The outcome of this study will explore the role of neuron-specific as well as feed-forward microglial IL1 signaling in tauopathies and provide mechanistic insights on IL1R/MyD88 signaling at multiple cellular levels as a therapeutic target against human tauopathies.

描述（由申请人提供）：微管相关蛋白tau（MAPT）和神经变性的突出丝状包涵体是许多神经变性tau蛋白病的标志。尽管这些tau蛋白病中的许多的确切病因仍然难以捉摸，但在神经病理学上，它们的特征在于过度磷酸化的MAPT的细胞内聚集、神经炎症和细胞死亡。越来越多的证据表明，神经炎症可能直接导致神经退行性tau蛋白病的病理生理学。然而，这些研究在很大程度上是相关的，并且没有提供神经炎症在神经退行性疾病过程中的作用的直接证据。我们最近提供了令人信服的证据表明，神经炎症，细胞自主的小胶质细胞，加速MAPT磷酸化，聚集和行为障碍的小鼠模型的tau蛋白病（hTau）。值得注意的是，当小鼠缺乏小胶质细胞特异性fractalkine受体CX 3CR 1时，小胶质细胞活化对MAPT病理学的影响增强。我们还证明，由反应性小胶质细胞释放的白细胞介素-1（IL-1）通过激活神经元IL-1受体（IL-1 R）和p38丝裂原活化蛋白激酶（p38 MAPK）途径诱导原代神经元MAPT磷酸化。总之，这些结果表明，神经元IL 1 R/p38 MAPK的抑制可能代表了人类tau蛋白病的独特的潜在药物靶标。许多研究已经确定髓样分化初级应答基因88（MyD 88）是IL 1 R的关键下游衔接蛋白以及p38 MAPK活化的上游。最近的研究表明，MyD 88的遗传缺陷对缺氧诱导的脑损伤和全身性炎症小鼠模型具有保护作用。然而，MyD 88在介导IL 1诱导的MAPT病理中的作用尚不清楚。同样不清楚的是小胶质细胞衍生的IL 1是否反馈到小胶质细胞本身以诱导促成神经元MAPT病理和神经变性的自传播IL 1信号传导。基于我们最近的研究，即小胶质细胞特异性神经炎症足以通过IL 1-p38 MAPK通路诱导神经元MAPT病理和认知障碍，本发明的目标是通过靶向的细胞特异性缺失MyD 88来特异性靶向小胶质细胞特异性和神经元特异性IL 1 R信号传导，并研究其对p38 MAPK激活、MAPT病理、神经炎症、在两个特定目标下，在tau蛋白病（hTau）的小鼠模型中研究神经变性和认知功能。1)研究hTau小鼠前脑神经元限制性缺失MyD 88对不同年龄MAPT病理、神经炎症、神经退行性变和行为功能的影响。2)研究小胶质细胞限制性MyD 88缺失对不同年龄hTau小鼠MAPT病理、神经炎症、神经退行性变和行为功能的影响。这些研究将提供对IL 1 R/MyD 88信号传导在tau蛋白病中的细胞自主贡献的更好理解，并确定MyD 88是否可以作为针对人类tau蛋白病中炎症介导的MAPT病理的潜在治疗靶标。 公共卫生相关性：越来越多的证据表明，与年龄相关的脑炎症可能在许多人类tau蛋白病中的tau蛋白介导的神经退行性变中起重要作用。我们小组最近的一项研究提供了令人信服的证据，表明小胶质细胞特异性神经炎症加速了tau蛋白病人源化小鼠模型（hTau）中的tau病理和认知障碍。值得注意的是，从活化的小胶质细胞释放的白细胞介素-1（IL 1）负责通过IL 1受体（IL 1 R）信号通路上调神经元p38丝裂原活化蛋白激酶（p38 MAPK）和tau蛋白过度磷酸化。在当前的研究中，将在人tau蛋白病的hTau小鼠模型中研究前脑神经元和小胶质细胞特异性消融IL 1 R信号传导（通过缺失IL 1 R受体蛋白MyD 88）对tau病理学、神经变性和行为功能的影响。这项研究的结果将探索神经元特异性以及前馈小胶质细胞IL 1信号传导在tau蛋白病中的作用，并在多个细胞水平上提供关于IL 1 R/MyD 88信号传导作为人类tau蛋白病治疗靶点的机制见解。